Rudy Tanzi, Ph.D.

Dr. Rudolph Tanzi is the Vice-Chair of Neurology and Director of the Genetics and Aging Research Unit at Massachusetts General Hospital, and serves as the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School.

Dr. Tanzi co-discovered three of the first Alzheimer’s disease genes and has identified several others in the Alzheimer’s Genome Project, which he directs. He also discovered the Wilson’s disease gene and participated in the discovery of several other neurological disease genes. Most recently, he has used AD genes to create a three- dimensional human stem cell-derived neural culture system that recapitulates AD plaque and tangle pathology. Using this system, Dr. Tanzi is also developing therapeutics for AD including gamma secretase modulators and metal chaperones to lower beta-amyloid and tangle burden in the brain.

Dr. Tanzi has published nearly 500 research papers and has received the highest awards in his field, including the Metropolitan Life Foundation Award and Potamkin Prize. Most recently, he received the 2015 Smithsonian American Ingenuity Award and was named to the 2015 list of TIME100 Most Influential People in the World.

He co-authored the popular trade books “Decoding Darkness”, New York Times Bestseller, “Super Brain”, and “Super Genes” He was named by GQ magazine as a Rock Star of Science, and in his spare time, has played keyboards with the band Aerosmith, guitarist, Joe Perry, and singer, Chris Mann.

Funded Research

The goal of this project is to evaluate our new Alzheimer’s disease gene candidates for effects on Alzheimer’s pathology and related biological pathways, including APP processing, amyloid beta protein generation, tangle formation and cell death. These studies are being carried out as part of Phase II of the Alzheimer’s Genome Project (AGP) and entail functional analyses of the Alzheimer’s gene candidates identified in Phase I of the AGP.

Our current inability to prevent or delay Alzheimer’s disease (AD) and the expected increase in the prevalence of AD are predicted to give rise to a global AD pandemic. We recently have identified a novel pathway for amyloid beta (Abeta) clearance in the aging brain that is highly relevant to AD pathogenesis. In a very large family-based, genome-wide association study, we identified CD33 as a novel late-onset AD risk factor. CD33 encodes a transmembrane sialic acid-binding immunoglobulin-like lectin that regulates innate immunity.

This multidimensional investigation will seek to elucidate sex-linked factors that determine Alzheimer’s disease risk, age of onset and rate of progression, powerful information that would contribute to the pursuit of a cure for both sexes. Women make up more than two-thirds of the Alzheimer’s patient population, yet very little is known or understood about why this is the case or what it means about the disease’s mechanisms of action, risk factors and progression.

This application outlines a highly focused extension of an NIH-funded Blueprint Neurotherapeutics (BPN) U01 program to create more potent, soluble, brain penetrant, nontoxic small molecules known as soluble gamma-secretase modulators (SGSMs) that act to enhance the activity/processivity of y-secretase, thereby reducing the levels of Aβ42 and to a lesser extent Aβ40 while increasing the levels of shorter Abeta peptides (e.g., Aβ38 and Aβ37)

We will carry out Whole Genome Sequencing (WGS) of all subjects in the National Institute of Mental Health (NIMH) Alzheimer’s disease family sample (1,510 subjects; 437 AD families). We will identify functional DNA variants throughout the human genome that are inherited as risk factors for Alzheimer’s disease. We also will analyze DNA from brain samples of subjects who exhibited significant Alzheimer’s pathology at autopsy, but never suffered from dementia; this will allow us to identify protective gene variants as well.

The goal of this project is to determine whether the amylin (IAPP) protein has a role in innate immunity (similar to Abeta) in order to significantly advance our understanding of the origins of diabetes pathology and its possible linkage to Alzheimer’s disease.

We seek to evaluate the impact of candidate AD drugs on Abeta and tau pathology in human cellular AD models. In collaboration with Dr. Tanzi’s laboratory (Massachusetts General Hospital), we will test the impact of select candidate AD drugs on both Abeta and tau pathology in the 30 human neural cell culture models developed in Aim 4. In the first year, we found that SGSM41i, a candidate AD drug designed to specifically decrease the toxic Abeta42 generation, decreases not only the Abeta plaques but also the tau pathology in the 30 human cellular AD models.

This collaborative project will identify and characterize novel curcumin-like derivatives for the treatment and prevention of Alzheimer’s disease. The purpose of the study is to develop means of overcoming obstacles to rapid breakdown and creating methodologies for precisely delivering curcumin derivatives to appropriate locations within the brain.

Building on in vitro characterization of a novel series of soluable gamma-secretase modulators (SGSMs) funded by Cure Alzheimer’s Fund, the current project is a thorough pharmacological or in vivo examination of these molecules to identify the best or “lead” drug candidate.

Alzheimer’s disease (AD) is the most common form of dementia in the elderly afflicting over 20 million people worldwide. Two decades of findings from cell biology, genetic, neuropathological, biochemical and animal studies overwhelmingly point to the β-amyloid peptide (Aβ) as the key protein in the disease’s pathology (see review by Hardy and Selkoe, 20001). Aβ appears to be a soluble component of normal brain. However, in AD brain the peptide accumulates as β-amyloid, an insoluble semi-crystalline deposit that is the hallmark of the disease pathology.

A collaboration of members of the Research Consortium, a member of the Cure Alzheimer’s Fund Science Advisory Board and non-Cure Alzheimer’s Fund-affiliated researchers hypothesizes that an abnormal increase in levels of synaptic Abeta and, particularly, Abeta oligomers may lead to synaptic dysfunction, cognitive decline and eventually dementia. This highly innovative collaborative project will address how Abeta oligomers are formed and which types detrimentally impact synaptic dysfunction and neuronal survival in the brain.

While the mechanism of Aβ cytotoxicity remains contentious, evidence is accumulating that membrane permiabilization plays a key role in the pathological activity of the peptide. This study will focus on role of Aβ oligomerization in the Aβ-mediated disruption of lipid bilayers.

We have coined the term CAPS to describe cross-linked-Beta-amyloid protein species. CAPS, particularly dimeric forms, are highly neurotoxic. CAPS are also abundant in vivo, with dimeric species alone comprising as much as 40 percent of the total Abeta pool in late state AD brain. In this study we plan to screen compound libraries for potential therapeutic agents that attenuate the levels and/or cytotoxic activity of CAPS.